Summary Although memory dysfunction is a frequent symptom of traumatic brain injury (TBI), there are currently no effective treatments available for this persistent deficit. In addition, the neurophysiological basis of this disruption remains unknown, making rational treatment design difficult. Disruption of oscillations in memory encoding structures have been demonstrated in animal models of TBI, with loss of hippocampal theta a prominent finding. Restoration of theta using neuromodulation can also restore aspects of memory function in the hippocampus, suggesting that neurons in the hippocampus are still functional, but that coordination between them has been lost along with this organizing signal. New advances in electrode technology can reveal how encoding in the HC is changed post injury, how multiple neurons interact with oscillations, and how the decrease in HC theta has affected cells that use it to encode for spatial memory. The overall objective of the current application is to determine how the coding of memory in hippocampal and associated circuitry is disrupted following TBI, and how theta neuromodulation restores hippocampal function. Our central hypothesis is that TBI disrupts communication within the larger hippocampal network, including oscillatory interactions required for encoding and recall of memory in these connected regions. This hypothesis is based in part on our preliminary data demonstrating that neurons in the hippocampus do not properly fire synchronously with oscillations following injury. To test the above hypothesis, we will first determine the mechanism of theta disruption in the hippocampus following diffuse TBI and its effect on neuronal behavior. We hypothesize that axonal injury between theta generating structures leads to a loss of oscillatory organization in the hippocampus, and a compensatory response in CA1 neurons affects synchronization to theta. TBI may also lead to disruption in the oscillatory communication in the wider hippocampal network, including medial prefrontal cortex (mPFC), leading to spatial working memory dysfunction. We will therefore quantify disruption of neuronal coding and oscillations in this network in awake behaving rats following TBI, and determine the mechanism of neuromodulatory restoration of spatial memory. We will further test this hypothesis in a clinically relevant large animal model of mild TBI that produces diffuse axonal injury to determine whether connectivity disruption is sufficient to affect coordinated neuronal activity in the hippocampal-mPFC memory network. The proposed research will provide the first detailed analysis of disrupted neuronal coding and oscillatory interactions between brain regions underlying memory following TBI and their relationship to axonal injury. These experiments will also identify the effect of neuromodulation on these networks, leading to crucial mechanisms that can be translated in the future to preclinical and clinical TBI treatments. Identification of the mechanisms of neuronal and network disruption underlying memory dysfunction will allow for the development of targeted treatments for this common lingering cognitive deficit following TBI.